Background

In the global, Phase 3 HIMALAYA study (NCT03298451) in uHCC, a single priming dose of T plus regular interval D (STRIDE) significantly improved overall survival (OS) vs sorafenib (S), and D was noninferior to S (Abou-Alfa et al. NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2100070). HCC aetiology varies globally and may influence response to immunotherapy. HBV is predominant in most Asian countries, whereas HCV or nonviral aetiologies are more common in Japan and Western countries. Thus, we analysed outcomes in patients (pts) enrolled in Asia, excluding Japan.

Methods

OS, objective response rate (ORR), duration of response (DoR) and safety for STRIDE, D and S were assessed in pts in Asia (Hong Kong, India, South Korea, Taiwan, Thailand, Vietnam; minus Japan). OS hazard ratios (HRs) and confidence intervals (CIs) were calculated using a Cox proportional hazards model.

Results

The Asia subgroup included 479 pts randomised to STRIDE (n=156), D (n=167) or S (n=156); baseline demographic and disease characteristics were balanced across treatment arms. In Asia vs globally, 62% vs 31% of pts had HBV (HBsAg and/or anti-HBcAb + HBV DNA), 16% vs 27% had HCV (anti-HCV antibodies) and 22% vs 42% had nonviral aetiology. OS was improved for STRIDE vs S in Asia, consistent with the global population (Table). The OS HR for D vs S in Asia was similar to the global population. In Asia and globally, OS at 36 months, ORR and DoR were higher for STRIDE than for D or S. Outcomes in pts of Chinese descent (Hong Kong/Taiwan) were generally consistent with the full Asian subgroup. Grade 3 or 4 treatment-related adverse events were lower for STRIDE and D vs S in Asia (20% and 13% vs 31%) and globally (26% and 13% vs 37%) Table: 67O

Conclusions

STRIDE improved outcomes vs S for pts in Asia, consistent with the global population. These results support the benefits of STRIDE for pts with uHCC in the Asia-Pacific region, including Hong Kong and Taiwan.

Clinical trial identification

NCT03298451.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Claire Tinderholm, PhD, of CMC Connect, McCann Health Medical Communications, with funding from AstraZeneca, in accordance with Good Publications Practice (GPP3) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

S.L. Chan: Financial Interests, Personal, Advisory Board: Eisai, Astra-Zeneca, MSD; Financial Interests, Personal, Invited Speaker: Astra-Zeneca, MSD, Eisai, Roche, IPSEN, BMS, Bayer; Financial Interests, Personal, Research Grant: Eisai, MSD, IPSEN, Bayer, SIRTEX. M. Kudo: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Eli Liiy, Bayer, Takeda, MSD; Financial Interests, Institutional, Research Grant: Otsuka, Sumitomo Dainippon Pharma, EA Pharma, Taiho, Eisai, AbbVie, Gilead Sciences, Takeda, GE Healthcare, Chugai. B. Sangro: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Boston Scientific, Eisai, Ipsen, Roche, Sirtex, Terumo, Incyte, Bayer; Financial Interests, Personal, Invited Speaker: Roche, Sirtex, Eisai, Ipsen, BMS, Incyte, AstraZeneca, Bayer, Astra Zeneca, BMS, Boston Scientific, Roche, Sirtex; Financial Interests, Institutional, Research Grant: BMS, Sirtex; Financial Interests, Institutional, Invited Speaker: Adaptimmune; Non-Financial Interests, Personal, Invited Speaker: International Liver Cancer Association. R.K. Kelley: Financial Interests, Personal, Advisory Board, Compensation for service on advisory board in 2019: Genentech/Roche; Financial Interests, Personal, Other, IDMC membership 2018-2020: Genentech/Roche; Financial Interests, Personal, Advisory Board, 2020: Gilead, Exact Sciences; Financial Interests, Personal, Advisory Board, Advisory board member in 2021: Kinnate; Financial Interests, Institutional, Invited Speaker: Agios, Agios, Astra Zeneca, Astra Zeneca, Bayer, BMS, Eli Lilly, Exelixis, EMD Serono, Genentech/Roche, Merck, Merck, QED, Taiho, Novartis, Relay Therapeutics, Surface Oncology, LOXO Oncology; Financial Interests, Institutional, Research Grant: Partner Therapeutics; Non-Financial Interests, Personal, Advisory Role, IDMC chair and member: Genentech/Roche; Non-Financial Interests, Personal, Principal Investigator: Exelixis, Astra Zeneca. J. Furuse: Financial Interests, Personal, Other, Grant/ research support: Astellas, Chugai Pharma, Daiichi Sankyo, Eisai, Incyte Japan, J-Pharma, Merck Bio, Mochida, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Sanofi, Sumitomo Dainippon Bayer, and Yakult Honsha; Financial Interests, Personal, Other, Consulting fees: Bayer, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Eli Lilly Japan, Incyte Japan, Kyowa Hakko Kirin, MSD, Mylan EPD, Novartis Pharma, Ono Pharmaceutical, Pfizer, Sanofi, Servier Japan, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult Honsha. P. Sunpaweravong: Financial Interests, Personal, Advisory Board: Roche, Eisai, BMS, AstraZeneca, MSD, Ipsen, Pfizer; Financial Interests, Personal, Invited Speaker: Novartis, BMS, Mundipharma, Bayer. T. Yau: Financial Interests, Personal, Advisory Board, Honorarium: BMS, MSD, AstraZeneCa, Roche. T. Kawaoka: Financial Interests, Institutional, Other, Research funding: AstraZeneca. A. Cheng: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, BAYER Healthcare, AstraZeneca, Genentech/Roche, Merck Sharp Dohme, BeiGene, Ltd., EXELIXIS Ltd., IPSEN Innovation, F. Hoffmanna-La ROCHE Ltd.; Financial Interests, Personal, Invited Speaker: Eisai, Ono Pharmaceutical, Bayer Yakuhin Ltd., Novartis, Amgen Taiwan, Chugai Pharmaceutical; Financial Interests, Personal, Other, Travel: IQVIA. S. Azevedo: Financial Interests, Personal, Other, Grant and research support: Amgen, AstraZeneca, Bristol Myers Squibb, MSD, Novartis, Pfizer, and Roche/Genentech. M.E. Reig Monzon: Financial Interests, Personal, Other, Consultancy: Bayer - Shering Pharma, Ipsen, BMS, Roche, AstraZeneca, Lilly, BTG; Financial Interests, Personal, Other, Paid conferences: Bayer - Shering Pharma, BMS, Roche, Lilly, Gillead, Eisai; Financial Interests, Personal, Research Grant: Bayer - Shering Pharma, Ipsen. E. Assenat: Financial Interests, Personal, Other, Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca, Ipsen, Bayer, Roche. M. Yarchoan: Financial Interests, Personal, Advisory Board: Genentech, Eisai, Exelixis, AstraZeneca, Replimune, Hepion; Financial Interests, Institutional, Research Grant, John Hopkins: Genentech, Bristol Myers Squibb, Exelixis, Incyte. A.R. He: Financial Interests, Personal, Other, Advisory Board meeting on management of biliary cancer and HCC: AstraZeneca. M. Makowsky: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Gupta: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Negro: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. G.K. Abou-Alfa: Financial Interests, Personal, Advisory Board: Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Boehringer Ingelheim, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Helsinn, Incyte, Ipsen, Merck, Nerviano, Newbridge, Novartis, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector, Yiviva; Financial Interests, Personal, Other, IP License: PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No.: 61/804,907; Filed: March 25, 2013; Financial Interests, Institutional, Research Grant: Arcus, AstraZeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, Yiviva; Non-Financial Interests, Personal, Principal Investigator: Astra Zeneca, Yiviva, QED. All other authors have declared no conflicts of interest.

Background

In the double-blind, Phase 3 TOPAZ-1 study (NCT03875235), overall survival (OS) with D+GC versus PBO+GC was significantly improved in patients (pts) with previously untreated advanced BTC (Oh et al. NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2200015). An exploratory objective of the TOPAZ-1 study was to assess efficacy outcomes by tumour mutations.

Methods

Eligible pts were randomised 1:1 to receive D+GC or PBO+GC. Genomic profiling of formalin-fixed paraffin-embedded tumour tissues from biomarker-evaluable pts (BEPs) was performed using the FoundationOne® panel (Foundation Medicine, Cambridge, MA). Mutation prevalence and outcomes based on the 25 February 2022 data cut-off were descriptively assessed across subtype and geographical region subgroups.

Results

BEPs comprised 441/685 pts (64% of full analysis set). TP53, CDKN2A/CDKN2B/MTAP on chromosome 9p21, KRAS and ARID1A were the most frequently altered genes. Mutation prevalence varied by subtype, consistent with previous reports. OS hazard ratios (HR) with D+GC versus PBO+GC for pts with mutant or wild-type genes that are clinically actionable with prevalence greater than 3% are shown (Table). While prevalence is low for many of the alterations, HRs<1 are noted for all clinically actionable mutant subtypes except ERBB2 alterations. However, response rates were nominally higher in the majority of D+GC vs PBO+GC groups, including ERBB2 alterations, suggesting activity in these subgroups Table: 68O

Prevalence of clinically actionable alterations in TOPAZ-1 by primary tumour location and geographical region

Conclusions

BTC mutation prevalence in TOPAZ-1 by primary tumour location and geographical region was consistent with other studies. Although pt numbers were low and the confidence intervals were broad, pts with clinically actionable alterations (IDH1, BRAF and BRCA1/2 mutations and FGFR2 rearrangements) appeared to benefit from D+GC.

Clinical trial identification

NCT03875235.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Elaine Groat, PhD, of CMC Connect, McCann Health Medical Communications, with funding from AstraZeneca, in accordance with Good Publication Practice (GPP3) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.W. Valle: Financial Interests, Personal, Advisory Board: Astra-Zeneca, Agios, QED, NuCana BioMed, Servier, Image Equipment Ltd. (AAA), Hutchinson Medipharma, Zymeworks, Sirtex, Baxter, Autem, Hutchinson Medipharma; Financial Interests, Personal, Invited Speaker: Ipsen, Mylan, Incyte; Financial Interests, Institutional, Research Grant, Grant funding for ABC-12 study: AstraZeneca; Financial Interests, Institutional, Research Grant, University of Manchester: RedX. L. Antonuzzo: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Amgen, MSD, BMS; Financial Interests, Institutional, Other, research founding: novartis. D. Tougeron: Financial Interests, Personal, Advisory Board: AstraZeneca, Sanofi, AMGEN, MSD, Roche, Servier, Servier, Pierre Fabre. B.J. Tan: Financial Interests, Institutional, Other, Grant and research support: Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelixis, and Zymeworks. M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Ono, Takeda, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, NIHON Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, NIHON Servier, Takeda; Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, NIHON SERVIER, Delta-Fly Pharma, Syneos Health, Merus.N.V. V. Guthrie, P. McCoon, Y.S. Lee, N. Rokutanda: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Watras: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of AstraZeneca Poland: AstraZeneca. G. Cohen: Financial Interests, Personal, Full or part-time Employment, I am a full time employee of AstraZeneca. Position is Global Clinical Lead in Immuno-oncology: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Own stock in the company as an employee: AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitor plus chemotherapy (chemo) as first-line treatment improves efficacy in oesophageal squamous cell carcinoma (ESCC) patients, yet the optimal target population for this combination therapy is uncertain, and the treatment outcomes are still unsatisfactory. Efficacy and safety of serplulimab, a novel anti-PD-1 antibody, were evaluated in combination with chemo in patients with previously untreated, advanced, PD-L1-positive (CPS ≥1) ESCC.

Methods

Eligible patients were enrolled in this double-blind phase 3 trial (NCT03958890) and randomised 2:1 to receive serplulimab 3 mg/kg or placebo combined with cisplatin 50 mg/m² and 5-fluorouracil 1200 mg/m² daily on days 1–2 intravenously every 2 weeks. Randomisation was stratified by PD-L1 expression levels, age, and disease status. Co-primary endpoints were PFS assessed by the independent radiology review committee and OS in the ITT population.

Results

Between June 19, 2019, and Dec 17, 2021, 551 patients were randomised to receive serplulimab plus chemo (n=368) or placebo plus chemo (n=183). Median follow-up duration was 14.9 months. Median PFS (final analysis) was significantly longer in serplulimab plus chemo group (5.8 months [95% CI 5.7–6.9]) than that in placebo plus chemo group (5.3 months [95% CI 4.3–5.6]; HR 0.60, 95% CI 0.48–0.75; p<0.0001). Median OS (interim analysis) was also significantly improved with the addition of serplulimab (15.3 months [95% CI 14.0–18.6] versus 11.8 months [95% CI 9.7–14.0]; HR 0.68, 95% CI 0.53–0.87; p=0.0020). Grade ≥3 treatment-related AEs occurred in 201 (52.6%) patients receiving serplulimab plus chemo and in 81 (48.2%) receiving placebo plus chemo, with deaths due to treatment-related AEs occurring in 11 (2.9%) and 3 (1.8%) patients in the respective groups.

Conclusions

Serplulimab in combination with chemo administered every 2 weeks significantly improved PFS (final) and OS (interim) compared with chemo alone in first-line therapy of PD-L1-positive advanced ESCC, which can be considered as a new standard option for this patient population.

Clinical trial identification

CTR20190911, NCT03958890.

Editorial acknowledgement

Shiqi Zhong and Chen Hu of Shanghai Henlius Biotech, Inc.

Legal entity responsible for the study

Shanghai Henlius Biotech, Inc.

Funding

Shanghai Henlius Biotech, Inc.

Disclosure

J. Huang: Non-Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme (MSD), Roche. Q. Wang: Financial Interests, Personal, Full or part-time Employment: Shanghai Henlius Biotech, Inc. J. Zhu: Financial Interests, Personal, Full or part-time Employment: Shanghai Henlius Biotech, Inc. All other authors have declared no conflicts of interest.

Background

TIS, an anti-PD-1 antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo (PBO) + chemo in patients (pts) with advanced or metastatic ESCC, with a manageable safety profile, at interim analysis of the Phase 3 RATIONALE-306 study. We report data from the Asia subgroup.

Methods

Adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV Q3W, with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) per INV; and safety.

Results

Of 649 randomized pts, 486 (74.9%) were from Asia (243 pts per arm). At data cutoff (Feb 28, 2022), the median (m) follow-up in the Asia subgroup was 16.5 months (mo) in Arm A vs 10.6 mo in Arm B. OS (mOS 18.3 vs 11.5 mo; unstratified HR 0.67 [95% CI 0.54, 0.84]) and PFS (mPFS 7.2 vs 5.6 mo; unstratified HR 0.62 [95% CI 0.50, 0.76]) were improved in Arm A vs B, respectively. Arm A had higher ORR (64.2% vs 42.8%, odds ratio 2.40 [95% CI 1.66, 3.45]) and longer mDoR (7.1 mo [95% CI 5.6, 8.4] vs 5.6 mo [95% CI 4.4, 7.1]) than Arm B. Similar proportions of pts in Arm A vs B had ≥1 treatment-related AEs (TRAEs; 97.5% vs 98.8%), ≥Grade 3 TRAEs (70.1% vs 68.3%), and TRAEs leading to death (2.1% vs 1.2%), respectively. Serious TRAEs occurred in 29.9% vs 19.8% of pts, and discontinuation due to treatment-emergent AEs occurred in 28.2% vs 18.1%, in Arm A vs B, respectively.

Conclusions

In the Asia subgroup, 1L TIS + chemo demonstrated clinically meaningful improvement in OS and improvements in PFS, ORR, and DoR vs PBO + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population.

Clinical trial identification

NCT03783442.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Helena Crisford, MSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

K. Kato: Financial Interests, Personal and Institutional, Advisory Board: ONO pharmaceuticals, Bristol Myers Squibb, Merck & Co., Beigene; Financial Interests, Personal and Institutional, Other, Honoraria: ONO pharmaceuticals, Bristol Myers Squibb, Merck & Co.; Financial Interests, Personal and Institutional, Principal Investigator: ONO pharmaceuticals, Bristol Myers Squibb, Merck & Co., Beigene; Financial Interests, Personal and Institutional, Research Grant: ONO pharmaceuticals, Bristol Myers Squibb; Financial Interests, Personal and Institutional, Speaker’s Bureau: ONO pharmaceuticals, Bristol Myers Squibb. H. Yoon: Financial Interests, Personal, Advisory Board: OncXerna, Merck, Zymeworks, MacroGenics, BMS, BeiGene, AstraZeneca; Financial Interests, Personal, Other, Steering committee: Merck, MacroGenics, BeiGene; Financial Interests, Personal, Invited Speaker: BeiGene; Financial Interests, Personal, Research Grant: BeiGene; Financial Interests, Personal, Other, Education symposium: BeiGene; Financial Interests, Personal, Sponsor/Funding: Merck, BMS, MacroGenics, BeiGene, Boston Biomedical, Elevar Therapeutics, CARsgen. R. Hubner: Financial Interests, Personal, Advisory Role: Novartis, Beigene. S.R. Park: Financial Interests, Personal and Institutional, Advisory Board: Genome & Company; Financial Interests, Institutional, Funding: ImmuneOncia. L. Shen: Financial Interests, Institutional, Funding: Jacobio Pharmaceuticals, Baiji Shenzhou (Beijing) Biotechnology Co. Ltd., Yaojie Ankang (Nanjing) Technology Co. Ltd., Beihai Kangcheng (Beijing) Medical Technology, ZaiLab Pharmaceutical (Shanghai), Qilu Pharmaceutical, Beijing Xiantong Biomedical Techno; Financial Interests, Personal, Advisory Role: Mingji biopharmaceutical, Haichuang pharmaceutical, Herbour biomed; Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa Hengrui, CSTONE pharmaceutical ZaiLab; Financial Interests, Personal, Advisory Board: MSD, Merk, BMS, BI Sanofi, Roche, Servier. T. Kojima: Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb, Ono Pharmaceutical Co. Ltd., MSD K.K., OncolysBioPharma Inc., Merck Biopharma Co. Ltd., Astellas Pharma Inc.; Financial Interests, Personal and Institutional, Invited Speaker: OncolysBioPharma Inc.; Financial Interests, Personal and Institutional, Research Grant: Bristol Myers Squibb, Ono Pharmaceutical Co. Ltd., MSD K.K., Taiho Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd.; Financial Interests, Personal and Institutional, Writing Engagements: MSD K.K.; Financial Interests, Institutional, Research Grant: BeiGene Ltd., EPS Corporation, Amgen Inc., Shionogi & Co. Ltd., Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Parexel International, Merck Biopharma Co. Ltd. L. Wang: Other, Personal and Institutional, Full or part-time Employment, Employee: BeiGene. Y. Peng: Financial Interests, Personal and Institutional, Full or part-time Employment: BeiGene (Shanghai) Co., Ltd. L. Li: Financial Interests, Personal, Full or part-time Employment: BeiGene (Beijing) Co., Ltd., Beijing, China; Financial Interests, Personal, Stocks/Shares: BeiGene (Beijing) Co., Ltd., Beijing, China; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BeiGene (Beijing) Co., Ltd., Beijing, China; Financial Interests, Personal, Training: BeiGene (Beijing) Co., Ltd., Beijing, China. All other authors have declared no conflicts of interest.